Clinically Meaningful Improvement in the treatment of Negative Symptoms of Schizophrenia: The Case of Roluperidone

Background. Clinical meaningfulness in schizophrenia trials requires evidence that symptom change is recognizable in clinical practice. Established anchors include a 1 point minimal improvement on the CGI-S and a 7 to 10-point minimal improvement on the Personal and Social Performance scale (PSP), alongside a minimal improvement of 20% on the PANSS negative symptom factor score (NSFS) conventionally applied in negative-symptom trials. Methods. These clinically meaningful anchors were applied as benchmarks to pooled 12 week completer data from two randomized, placebo-controlled trials of roluperidone in adults with schizophrenia and moderate to severe negative symptoms. Results. Roluperidone was associated with higher responder rates than placebo on all three endpoints: at least 20% NSFS improvement (66/176 [38%] vs 39/182 [21%]; RR=1.75, 95% CI: 1.25 to 2.45; p=0.0008), at least 1 point CGI-S improvement (68/167 [41%] vs 48/177 [27%]; RR=1.50, 95% CI: 1.11 to 2.03; p=0.0077), and at least 10 point PSP improvement (63/176 [36%] vs 44/181 [24%]; RR=1.47, 95% CI: 1.06 to 2.04; p=0.018). Effects were consistent across symptoms, global-severity, and functional outcomes, with no evidence of heterogeneity between studies. Conclusions. Across all three anchor criteria, roughly 1.5 to 1.75 times as many patients treated with roluperidone as with placebo reached thresholds of improvement that clinicians and patients would recognize as clinically meaningful, supporting its relevance for persistent negative symptoms in schizophrenia.